This invention relates generally to modulators of chemokine receptor activity, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and prevention of inflammatory diseases such as asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis.
Chemokines are chemotactic cytokines, of molecular weight 6-15 kDa, that are released by a wide variety of cells to attract and activate, among other cell types, macrophages, T and B lymphocytes, eosinophils, basophils and neutrophils (reviewed in Luster, New Eng. J Med., 338, 436-445 (1998) and Rollins, Blood, 90, 909-928 (1997)). There are two major classes of chemokines, CXC and CC, depending on whether the first two cysteines in the amino acid sequence are separated by a single amino acid (CXC) or are adjacent (CC). The CXC chemokines, such as interleukin-8 (IL-8), neutrophil-activating protein-2 (NAP-2) and melanoma growth stimulatory activity protein (MGSA) are chemotactic primarily for neutrophils and T lymphocytes, whereas the CC chemokines, such as RANTES, MIP-1xcex1, MIP-1xcex2, the monocyte chemotactic proteins (MCP-1, MCP-2, MCP-3, MCP-4, and MCP-5) and the eotaxins (-1, -2, and -3) are chemotactic for, among other cell types, macrophages, T lymphocytes, eosinophils, dendritic cells, and basophils. There also exist the chemokines lymphotactin-1, lymphotactin-2 (both C chemokines), and fractalkine (a CXXXC chemokine) that do not fall into either of the major chemokine subfamilies.
The chemokines bind to specific cell-surface receptors belonging to the family of G-protein-coupled seven-transmembrane-domain proteins (reviewed in Horuk, Trends Pharm. Sci., 15, 159-165 (1994)) which are termed xe2x80x9cchemokine receptors.xe2x80x9d on binding their cognate ligands, chemokine receptors transduce an intracellular signal through the
associated trimeric G proteins, resulting in, among other responses, a rapid increase in intracellular calcium concentration, changes in cell shape, increased expression of cellular adhesion molecules, degranulation, and promotion of cell migration. There are at least ten human chemokine receptors that bind or respond to CC chemokines with the following characteristic patterns: CCR-1 (or xe2x80x9cCKR-1xe2x80x9d or xe2x80x9cCC-CKR-1xe2x80x9d) [MIP-1xcex1, MCP-3, MCP-4, RANTES] (Ben-Barruch, et al., Cell, 72, 415-425 (1993), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-2A and CCR-2B (or xe2x80x9cCKR-2Axe2x80x9d/xe2x80x9cCKR-2Bxe2x80x9d or xe2x80x9cCC-CKR-2Axe2x80x9d/xe2x80x9cCC-CKR-2Bxe2x80x9d) [MCP-1, MCP-2, MCP-3, MCP-4, MCP-5] (Charo et al., Proc. Natl. Acad. Sci. USA, 91, 2752-2756 (1994), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-3 (or xe2x80x9cCKR-3xe2x80x9d or xe2x80x9cCC-CKR-3xe2x80x9d) [eotaxin-1, eotaxin-2, RANTES, MCP-3, MCP-4] (Combadiere, et al., J. Biol. Chem., 270, 16491-16494 (1995), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-4 (or xe2x80x9cCKR-4xe2x80x9d or xe2x80x9cCC-CKR-4xe2x80x9d) [TARC, MIP-1xcex1, RANTES, MCP-1] (Power et al., J. Biol. Chem., 270, 19495-19500 (1995), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-5 (or xe2x80x9cCKR-5xe2x80x9d OR xe2x80x9cCC-CKR-5xe2x80x9d) [MIP-1xcex1, RANTES, MIP-1xcex2 (Sanson, et al., Biochemistry, 35, 3362-3367 (1996)); CCR-6 (or xe2x80x9cCKR-6xe2x80x9d or xe2x80x9cCC-CKR-6xe2x80x9d) [LARC] (Baba et al., J. Biol. Chem., 272, 14893-14898 (1997)); CCR-7 (or xe2x80x9cCKR-7xe2x80x9d or xe2x80x9cCC-CKR-7xe2x80x9d) [ELC] (Yoshie et al., J. Leukoc. Biol. 62, 634-644 (1997)); CCR-8 (or xe2x80x9cCKR-8xe2x80x9d or xe2x80x9cCC-CKR-8xe2x80x9d ) [I-309, TARC, MIP-1xcex2] (Napolitano et al., J. Immunol., 157, 2759-2763 (1996), Bernardini et al., Eur. J. Immunol., 28, 582-588 (1998)); and CCR-10 (or xe2x80x9cCKR-10xe2x80x9d or xe2x80x9cCC-CKR-10xe2x80x9d) [MCP-1, MCP-3] (Bonini et al, DNA and Cell Biol., 16, 1249-1256 (1997)).
In addition to the mammalian chemokine receptors, mammalian cytomegaloviruses, herpesviruses and poxviruses have been shown to express, in infected cells, proteins with the binding properties of chemokine receptors (reviewed by Wells and Schwartz, Curr. Opin. Biotech., 8, 741-748 (1997)). Human CC chemokines, such as RANTES and MCP-3, can cause rapid mobilization of calcium via these virally encoded receptors. Receptor expression may be permissive for infection by allowing for the subversion of normal immune system surveillance and response to infection. Additionally, human chemokine receptors, such as CXCR4, CCR2, CCR3, CCR5 and CCR8, can act as co-receptors for the infection of mammalian cells by microbes as with, for example, the human immunodeficiency viruses (HIV).
Chemokine receptors have been implicated as being important mediators of inflammatory, infectious, and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. For example, the chemokine receptor CCR-3 plays a pivotal role in attracting eosinophils to sites of allergic inflammation and in subsequently activating these cells. The chemokine ligands for CCR-3 induce a rapid increase in intracellular calcium concentration, increased expression of cellular adhesion molecules, cellular degranulation, and the promotion of eosinophil migration. Accordingly, agents which modulate chemokine receptors would be useful in such disorders and diseases. In addition, agents which modulate chemokine receptors would also be useful in infectious diseases such as by blocking infection of CCR3 expressing cells by HIV or in preventing the manipulation of immune cellular responses by viruses such as cytomegaloviruses.
A substantial body of art has accumulated over the past several decades with respect to substituted piperidines and pyrrolidines. These compounds have implicated in the treatment of a variety of disorders.
WO 98/25604 describes spiro-substituted azacycles which are useful as modulators of chemokine receptors: 
wherein R1 is C1-6 alkyl, optionally substituted with functional groups such as xe2x80x94NR6CONHR7, wherein R6 and R7 may be phenyl further substituted with hydroxy, alkyl, cyano, halo and haloalkyl. Such spiro compounds are not considered part of the present invention.
WO 95/13069 is directed to certain piperidine, pyrrolidine, and hexahydro-1H-azepine compounds of general formula: 
wherein A may be substituted alkyl or Z-substituted alkyl, with Zxe2x95x90NR6a or O. Compounds of this type are claimed to promote the release of growth hormone in humans and animals.
WO 93/06108 discloses pyrrolobenzoxazine derivatives as 5-hydroxytryptamine (5-HT) agonists and antagonists: 
wherein A is lower alkylene and R4 may be phenyl optionally substituted with halogen.
U.S. Pat. No. 5,668,151 discloses Neuropeptide Y (NPY) antagonists comprising 1,4-dihydropyridines with a piperidinyl or tetrahydropyridinyl-containing moiety attached to the 3-position of the 4-phenyl ring: 
wherein B may be NH, NR1, O, or a bond, and R7 may be substituted phenyl, benzyl, phenethyl and the like.
Patent publication EP 0 903 349 A2 discloses CCR-3 receptor antagonists comprising cyclic amines of the following structure: 
wherein T and U may be both nitrogen or one of T and U is nitrogen and the other is carbon and E may be xe2x80x94NR6CONR5xe2x80x94 and others.
These reference compounds are readily distinguished structurally by either the nature of the urea functionality, the attachment chain, or the possible substitution of the present invention. The prior art does not disclose nor suggest the unique combination of structural fragments which embody these novel piperidine amides as having activity toward the chemokine receptors.
Accordingly, one object of the present invention is to provide novel agonists or antagonists of CCR-3, or pharmaceutically acceptable salts or prodrugs thereof.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method for treating inflammatory diseases and allergic disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide novel piperidine amides for use in therapy.
It is another object of the present invention to provide the use of novel piperidine amides for the manufacture of a medicament for the treatment of allergic disorders.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors"" discovery that compounds of formula (I): 
or stereoisomers or pharmaceutically acceptable salts thereof, wherein E, Z, M, J, K, L, Q, R1, R2, and R3 are defined below, are effective modulators of chemokine activity.
[1] Thus, in a first embodiment, the present invention provides novel compounds of formula (I): 
or stereoisomers or pharmaceutically acceptable salts thereof, wherein:
M is absent or selected from CH2, CHR5, CHR13, CR13R13, and CR5R13;
Q is selected from CH2, CHR5, CHR13, CR13R13, and CR5R13;
K is selected from CH2, CHR5 and CHR6;
J and L are independently selected from CH2, CHR5, CHR6, CR6R6 and CR5R6;
with the provisos:
1) at least one of M, J, K, L, or Q contains an R5; and
2) when M is absent, J is selected from CH2, CHR5, CHR13, and CR5R13;
Z is selected from O, S, NR1a, C(CN)2, CH(NO2), and CHCN;
R1a is selected from H, C1-6 alkyl, C3-6 cycloalkyl, CONR1bR1b, OR1b, CN, NO2, and (CH2)wphenyl;
R1b is independently selected from H, C1-3 alkyl, C3-6 cycloalkyl, and phenyl;
E is xe2x80x94(Cxe2x95x90O)xe2x80x94(CR9R10)vxe2x80x94(CR11R12)xe2x80x94, xe2x80x94(SO2)xe2x80x94(CR9R10)vxe2x80x94(CR11R12)xe2x80x94, 
Ring A is a C3-8 carbocyclic residue;
R2 is selected from H, C1-8 alkyl, C3-8 alkenyl, C3-8 alkynyl, and a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 Ra;
Ra, at each occurrence, is selected from C1-4 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, (CF2)rCF3, NO2, CN, (CH2)rNRbRb, (CH2)rOH, (CH2)rORc, (CH2)rSH, (CH2)rSRc, (CH2)rC(O)Rb, (CH2)rC(O)NRbRb, (CH2)rNRbC(O)Rb, (CH2)rC(O)ORb, (CH2)rOC(O)Rc, (CH2)rCH(xe2x95x90NRb)NRbRb, (CH2)rNHC(xe2x95x90NRb)NRbRb, (CH2)rS(O)pRc, (CH2)rS(O)2NRbRb, (CH2)rNRbS(O)2Rc, and (CH2)rphenyl;
Rb, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl;
Rc, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, and phenyl;
R3 is selected from a(CR3xe2x80x2R3xe2x80x3)rxe2x80x94C3-8 carbocyclic residue substituted with 0-5 R15; a (CR3xe2x80x2R3xe2x80x3)rxe2x80x94C9-10 carbocyclic residue substituted with 0-4 R15; and a (CR3xe2x80x2R3xe2x80x3)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R15;
R3xe2x80x2 and R3xe2x80x3, at each occurrence, are selected from H, C1-6 alkyl, (CH2)rC3-6 cycloalkyl, and phenyl;
R5 is selected from a (CR5xe2x80x2R5xe2x80x3)txe2x80x94C3-10 carbocyclic residue substituted with 0-5 R16 and a (CR5xe2x80x2R5xe2x80x3)t-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R16;
R5xe2x80x2 and R5xe2x80x3, at each occurrence, are selected from H, C1-6 alkyl, (CH2)rC3-6 cycloalkyl, and phenyl;
R6, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, (CF2)rCF3, CN, (CH2)rNR6aR6axe2x80x2, (CH2)rOH, (CH2)rOR6b, (CH2)rSH, (CH2)rSR6b, (CH2)rC(O)OH, (CH2)rC(O)R6b, (CH2)rC(O)NR6aR6axe2x80x2, (CH2)rNR6dC(O)R6a, (CH2)rC(O)OR6b, (CH2)rOC(O)R6b, (CH2)rS(O)pR6b, (CH2)rS(O)2 NR6aR6axe2x80x2, (CH2)rNR6dS(O)2R6b, and (CH2)tphenyl substituted with 0-3 R6c;
R6a and R6axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R6c;
R6b, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R6c;
R6c, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, (CH2)rOH, (CH2)rSC1-5 alkyl, and (CH2)rNR6dR6d;
R6d, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
with the proviso that when any of J, K, or L is CR6R6 and R6 is halogen, cyano, nitro, or bonded to the carbon to which it is attached through a heteroatom, the other R6 is not halogen, cyano, or bonded to the carbon to which it is attached through a heteroatom;
R9, is selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, F, Cl, Br, I, NO2, CN, (CHRxe2x80x2)rOH, (CH2)rOR9d, (CH2)rSR9d, (CH2)rNR9aR9axe2x80x2, (CH2)rC(O)OH, (CH2)rC(O)R9b, (CH2)rC(O)NR9aR9axe2x80x2, (CH2)rNR9aC(O)R9a, (CH2)rNR9aC(O)H, (CH2)rC(O)OR9b, (CH2)rOC(O)R9b, (CH2)rOC(O)NR9aR9axe2x80x2, (CH2)rNR9aC(O)OR9b, (CH2)rS(O)pR9b, (CH2)rS(O)2NR9aR9axe2x80x2, (CH2)rNR9aS(O)2R9b, C1-6 haloalkyl, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R9c, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R9c;
R9a and R9axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R9e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R9e;
alternatively, R9a and R9axe2x80x2, along with the N to which they are attached, join to form a 5-6 membered heterocyclic system containing 1-2 heteroatoms selected from NR9g, O, and S and optionally fused with a benzene ring or a 6-membered aromatic heterocycle;
R9b, at each occurrence, is selected from C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-2 R9e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R9e;
R9c, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, (CF2)rCF3, NO2, CN, (CH2)rNR9fR9f, (CH2)rOH, (CH2)rOR9b, (CH2)rSR9b, (CH2)rC(O)OH, (CH2)rC(O)R9b, (CH2)rC(O)NR9fR9f, (CH2)rNR9fC(O)R9a, (CH2)rC(O)OR9b, (CH2)rOC(O)R9b, (CH2)rC(xe2x95x90NR9f)NR9fR9f, (CH2)rS(O)pR9b, (CH2)rNHC(xe2x95x90NR9f)NR9fR9f, (CH2)rS(O)2NR9fR9f, (CH2)rNR9fS(O)2R9b, and (CH2)rphenyl substituted with 0-3 R9e;
R9d, at each occurrence, is selected from C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, a C3-10 carbocyclic residue substituted with 0-3 R9c, and a 5-6 membered heterocyclic system containing 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-3 R9c;
R9e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR9fR9f, and (CH2)rphenyl, wherein the phenyl on the (CH2)rphenyl is substituted with 0-5 substituents selected from F, Cl, Br, I, NO2, C1-6alkyl, OH, and NR9fR9f;
R9f, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
R9g is selected from H, C1-6 alkyl, C3-6 cycloalkyl, (CH2)rphenyl, C(O)R9f, C(O)OR9h, and SO2R9h;
R9h, at each occurrence, is selected from C1-6 alkyl, and C3-6 cycloalkyl;
R10, is selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, F, Cl, Br, I, NO2, CN, (CHRxe2x80x2)rOH, (CH2)rOR10d, (CH2)rSR10d, (CH2)rNR10aR10axe2x80x2, (CH2)rC(O)OH, (CH2)rC(O)R10b, (CH2)rC(O)NR10aR10axe2x80x2, (CH2)rNR10aC(O)R10a, (CH2)rNR10aC(O)H, (CH2)rC(O)OR10b, (CH2)rOC(O)R10b, (CH2)rOC(O)NR10aR10axe2x80x2, (CH2)rNR10aC(O)OR10b, (CH2)rS(O)pR10b, (CH2)rS(O)2NR10aR10axe2x80x2, (CH2)rNR10aS(O)2R10b, C1-6 haloalkyl, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R10c, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R10c;
R10a  and R10axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R10e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R10e;
alternatively, R10a and R10axe2x80x2, along with the N to which they are attached, jointo form a 5-6 membered heterocyclic system containing 1-2 heteroatoms selected from NR11g, O, and S and optionally fused with a benzene ring or a 6-membered aromatic heterocycle;
R10b, at each occurrence, is selected from C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-2 R10e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R10e;
R10c, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, (CF2)rCF3, NO2, CN, (CH2)rNR10fR10f, (CH2)rOH, (CH2)rOR10b, (CH2)rSR10b, (CH2)rC(O)OH, (CH2)rC(O)R10b, (CH2)rC(O)NR10fR10f (CH2)rNR10fC(O)R10a, (CH2)rC(O)OR10b, (CH2)rOC(O)R10b, (CH2)rC(xe2x95x90NR10f)NR10fR10f, (CH2)rS(O)pR10b, (CH2)rNHC(xe2x95x90NR10f)NR10fR10f, (CH2)rS(O)2NR10fR10f, (CH2)rNR10fS(O)2R10b, and (CH2)rphenyl substituted with 0-3 R10e;
R10d, at each occurrence, is selected from C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, and a C3-10 carbocyclic residue substituted with 0-3 R10c;
R10e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR10fR10f, and (CH2)rphenyl;
R10f, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
R10g is selected from H, C1-6 alkyl, C3-6 cycloalkyl, (CH2)rphenyl, C(O)R10f, SO2R10h, and C(O)O R10h; R10h, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl;
alternatively, R9 and R10 join to form xe2x95x90O, a C3-10 cycloalkyl, a 5-6-membered lactone or lactam, or a 4-6-membered saturated heterocycle containing 1-2 heteroatoms selected from O, S, and NR10g and optionally fused with a benzene ring or a 6-membered aromatic heterocycle;
with the proviso that when either of R9 or R10 is bonded to the carbon to which it is attached through a heteroatom, then the other of R9 or R10 is not halogen, cyano, or bonded to the carbon to which it is attached through a heteroatom;
R11, is selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CRxe2x80x2R17)qOH, (CH2)qSH, (CRxe2x80x2R17)qOR11d, (CH2)qSR11d, (CRxe2x80x2R17)qNR11aR11axe2x80x2, (CH2)rC(O)OH, (CH2)rC(O)R11b, (CH2)rC(O)NR11aR11axe2x80x2, (CH2)qNR11aC(O)R11a, (CH2)qOC(O)NR11aR11axe2x80x2, (CH2)qNR11aC(O)OR11b, (CH2)qNR11aC(O)NHR11a, (CH2)rC(O)OR11b, (CH2)qOC(O)R11b, (CH2)qS(O)pR11b, (CH2)qS(O)2NR11aR11axe2x80x2, (CH2)qNR11aS(O)2R11b, C1-6 haloalkyl, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R11c, and a (Rxe2x80x2R17)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R11c;
R11a and R11axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R11e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R11e;
alternatively, R11a and R11axe2x80x2 along with the N to which they are attached, jointo form a 5-6 membered heterocyclic system containing 1-2 heteroatoms selected from NR11g, O, and S and optionally fused with a benzene ring or a 6-membered aromatic heterocycle;
R11b, at each occurrence, is selected from C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-2 R11e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R11e;
R11c, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, (CF2)rCF3, NO2, CN, (CH2)rNR11fR11f, (CH2)rOH, (CH2)rOC1-4 alkyl, (CH2)rSC1-4 alkyl, (CH2)rC(O)OH, (CH2)rC(O)R11b, (CH2)rC(O)NR11fR11f, (CH2)rNR11fC(O)R11a, (CH2)rC(O)OC1-4 alkyl, (CH2)rOC(O)R11b, (CH2)rC(xe2x95x90NR11f)NR11fR11f, (CH2)rNHC(xe2x95x90NR11f)NR11fR11f, (CH2)rS(O)pR11b, (CH2)rS(O)2NR11fR11f, (CH2)rNR11fS(O)2R11b, and (CH2)rphenyl substituted with 0-3 R11e;
R11d, at each occurrence, is selected from C1-6 alkyl, C3-6 alkenyl, C3-6 alkynyl, and a C3-10 carbocyclic residue substituted with 0-3 R11c;
R11e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, C1, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR11fR11f, and (CH2)rphenyl, wherein the phenyl on the (CH2)rphenyl is substituted with 0-5 substituents selected from F, Cl, Br, I, NO2, C1-6alkyl, OH, and NR9fR9f;
R11f, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
R11g is selected from H, C1-6 alkyl, C3-6 cycloalkyl, (CH2)rphenyl, C(O)R11fC(O)OR11h, and SO2R11h;
R11h, at each occurrence, is selected from C1-6 alkyl, and C3-6 cycloalkyl;
R12, is selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CHRxe2x80x2)qOH, (CH2)qSH, (CHRxe2x80x2)qOR12d, (CH2)qSR12d, (CHRxe2x80x2)qNR12aR12axe2x80x2, (CH2)rC(O)OH, (CH2)rC(O)R12b, (CH2)rC(O)NR12aR12axe2x80x2, (CH2)qNR12aC(O)R12a, (CH2)rOC(O)NR12aR12axe2x80x2, (CH2)rNR12aC(O)OR12b, (CH2)qNR12aC(O)NHR12a, (CH2)rC(O)OR12b, (CH2)qOC(O)R12b, (CH2)qS(O)pR12b, (CH2)qS(O)2NR12aR12axe2x80x2, (CH2)qNR12aS(O)2R12b, C1-6 haloalkyl, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R12c, and a (Rxe2x80x2R17)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R12c;
R12a and R12axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R12e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R12e;
alternatively, R12a and R12axe2x80x2, along with the N to which they are attached, join to form a 5-6 membered heterocyclic system containing 1-2 heteroatoms selected from NR12g, O, and S and optionally fused with a benzene ring or a 6-membered aromatic heterocycle;
R12b, at each occurrence, is selected from C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-2 R12e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R12e;
R12c, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, (CF2)rCF3, NO2, CN, (CH2)rNR12fR12f, (CH2)rOH, (CH2)rOC1-4 alkyl, (CH2)rSC1-4 alkyl, (CH2)rC(O)OH, (CH2)rC(O)R12b, (CH2)rC(O)NR12fR12f, (CH2)rNR12fC(O)R12a, (CH2)rC(O)OC1-4 alkyl, (CH2)rOC(O)R12b, (CH2)rC(xe2x95x90NR12f)NR12fR12f, (CH2)rNHC(xe2x95x90NR12f)NR12fR12f, (CH2)rS(O)pR12b, (CH2)rS(O)2NR12fR12f, (CH2)rNR12fS(O)2R12b, and (CH2)rphenyl substituted with 0-3 R12e;
R12d, at each occurrence, is selected from methyl, CF3, C2-6 alkyl substituted with 0-3 R12e, C3-6 alkenyl, C3-6 alkynyl, and a C3-10 carbocyclic residue substituted with 0-3 R12c;
R12e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR12fR12f, and (CH2)rphenyl;
R12f, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
R12g is selected from H, C1-6 alkyl, C3-6 cycloalkyl, (CH2)rphenyl, C(O)R12f, C(O)OR12h, and SO2R12h;
R12h, at each occurrence, is selected from C1-6 alkyl, and C3-6 cycloalkyl;
alternatively, R11 and R12 join to form a C3-10 cycloalkyl, a 5-6-membered lactone or lactam, or a 4-6-membered saturated heterocycle containing 1-2 heteroatoms selected from O, S, and NR11g and optionally fused with a benzene ring or a 6-membered aromatic heterocycle;
R13, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, (CF2)wCF3, (CH2)qNR13aR13axe2x80x2, (CHRxe2x80x2)qOH, (CH2)qOR13b, (CH2)qSH, (CH2)qSR13b, (CH2)wC(O)OH, (CH2)wC(O)R13b, (CH2)wC(O)NR13aR13axe2x80x2, (CH2)R13dC(O)R13a, (CH2)wC(O)OR13b, (CH2)qOC(O)R13b, (CH2)wS(O)pR13b, (CH2)wS(O)2NR13aR13axe2x80x2, (CH2)qNR13dS(O)2R13b, and (CH2)w-phenyl substituted with 0-3 R13c;
R13a and R13axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R13c;
R13b, at each occurrence, is selected from 0-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R13c;
R13c, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, (CH2)rOH, (CH2)rSC1-5 alkyl, and (CH2)rNR13dR13d;
R13d, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
R14, at each occurrence, is selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, NO2, CN, (CHRxe2x80x2)rNR14aR14axe2x80x2, (CHRxe2x80x2)rOH, (CHRxe2x80x2)rO(CHRxe2x80x2)rR14d, (CHRxe2x80x2)rSH, (CHRxe2x80x2)rC(O)H, (CHRxe2x80x2)rS (CHRxe2x80x2)rR14d, (CHRxe2x80x2)rC(O)OH, (CHRxe2x80x2)rC (O)(CHRxe2x80x2)rR14b, (CHRxe2x80x2)rC(O)NR14aR14axe2x80x2, (CHRxe2x80x2)rNR14fC(O)(CHRxe2x80x2)rR14b, (CHRxe2x80x2)rOC(O)NR14aR14axe2x80x2, (CHRxe2x80x2)rNR14fC(O)O(CHRxe2x80x2)rR14b, (CHRxe2x80x2)rC(O)O(CHRxe2x80x2)rR14d, (CHRxe2x80x2)rOC(O)(CHRxe2x80x2)rR14b, (CHRxe2x80x2)rC(xe2x95x90NR14f)NR14aR14axe2x80x2, (CHRxe2x80x2)rNHC(xe2x95x90NR14f)NR14fR14f, (CHRxe2x80x2)rS(O)p(CHRxe2x80x2)rR14b, (CHRxe2x80x2)rS(O)2NR14aR14axe2x80x2, (CHRxe2x80x2)rNR14fS(O)2(CHRxe2x80x2)rR14b, C1-6 haloalkyl, C2-8 alkenyl substituted with 0-3 Rxe2x80x2, C2-8 alkynyl substituted with 0-3 Rxe2x80x2, (CHRxe2x80x2)rphenyl substituted with 0-3 R14e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e, or two R14 substituents on adjacent atoms on ring A form to join a 5-6 membered heterocyclic system containing 1-3 heteroatoms selected from N, O, and S substituted with 0-2 R15e;
R14a and R14axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R14e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R14e;
R14b, at each occurrence, is selected from C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-3 R14e, and (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R14e;
R14d, at each occurrence, is selected from C3-8 alkenyl, C3-8 alkynyl, methyl, CF3, C2-6 alkyl substituted with 0-3 R14e, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-3 R14e, and a (CH2)r 5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R14e;
R14e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR14fR14f, and (CH2)rphenyl;
R14f, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl;
R15, at each occurrence, is selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, NO2, CN, (CRxe2x80x2R17)rNR15aR15axe2x80x2, (CRxe2x80x2R17)rOH, (CRxe2x80x2R17)rO(CHRxe2x80x2)rR15d, (CRxe2x80x2R17)rSH, (CRxe2x80x2R17)rC(O)H, (CRxe2x80x2R17)rS(CHRxe2x80x2)rR15d, (CRxe2x80x2R17)rC(O)OH, (CRxe2x80x2R17)rC(O)(CHRxe2x80x2)rR15b, (CRxe2x80x2R17)rC(O)NR15aR15axe2x80x2, (CRxe2x80x2R17)rNR15fC(O)(CHRxe2x80x2)rR15b, (CRxe2x80x2R17)rOC(O)NR15aR15a, (CRxe2x80x2R17)rNR15fC(O)O (CHRxe2x80x2)rR15b, (CRxe2x80x2R17)rNR15fC(O)NR15fR15f, (CRxe2x80x2R17)rC(O)O(CHRxe2x80x2)rR15d, (CRxe2x80x2R17)rOC(O)(CHRxe2x80x2)rR15b, (CRxe2x80x2R17)rC(xe2x95x90NR15f)NR15aR15axe2x80x2, (CRxe2x80x2R17)rNHC(xe2x95x90NR15f)NR15fR15f(CRxe2x80x2R17)rS(O)p(CHRxe2x80x2)rR15b, (CRxe2x80x2R17)rS(O)2NR15aR15axe2x80x2, (CRxe2x80x2R17)rNR15fS(O)2(CHRxe2x80x2)rR15b, C1-6 haloalkyl, C2-8 alkenyl substituted with 0-3 Rxe2x80x2, C2-8 alkynyl substituted with 0-3 Rxe2x80x2, (CRxe2x80x2R17)rphenyl substituted with 0-3 R15e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e;
R15a and R15axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R15e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e;
alternatively, R15a and R15axe2x80x2, along with the N to which they are attached, jointo form a 5-6 membered heterocyclic system containing 1-2 heteroatoms selected from NR15h, O, and S and optionally fused with a benzene ring or a 6-membered aromatic heterocycle;
R15b, at each occurrence, is selected from C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-3 R15e, and (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e;
R15d, at each occurrence, is selected from C3-8 alkenyl, C3-8 alkynyl, methyl, CF3, C2-6 alkyl substituted with 0-3 R15e, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-3 R15e, and a (CH2)r5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R15e;
R15e, at each occurrence, is selected from C1-6 alkyl, 2-cyanoethyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR15fR15f, (CH2)rphenyl, and a heterocycle substituted with 0-1 R15g, wherein the heterocycle is selected from imidazole, thiazole, oxazole, pyrazole, 1,2,4-triazole, 1,2,3-triazole, isoxazole, and tetrazole,;
R15f, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl;
R15g is selected from methyl, ethyl, acetyl, and CF3;
R15h is selected from H, C1-6 alkyl, C3-6 cycloalkyl, (CH2)rphenyl, C(O)R15f, C(O)OR15i, and SO2R15i;
R15i, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl;
R16, at each occurrence, is selected from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, NO2, CN, (CHRxe2x80x2)rNR16aR16axe2x80x2, (CHRxe2x80x2)rOH, (CHRxe2x80x2)rO(CHRxe2x80x2)rR16d, (CHRxe2x80x2)rSH, (CHRxe2x80x2)rC(O)H, (CHRxe2x80x2)rS(CHRxe2x80x2)rR16d, (CHRxe2x80x2)rC(O)OH, (CHRxe2x80x2)rC(O)(CHRxe2x80x2)rR16b, (CHRxe2x80x2)rC(O)NR16aR16axe2x80x2, (CHRxe2x80x2)rNR16fC(O)(CHRxe2x80x2)rR16b, (CHRxe2x80x2)rC(O)O(CHRxe2x80x2)rR16d, (CHRxe2x80x2)rOC(O)(CHRxe2x80x2)rR16b, (CHRxe2x80x2)rC(xe2x95x90NR16f)NR16aR16axe2x80x2, (CHRxe2x80x2)rNHC(xe2x95x90NR16f)NR16fR16f, (CHRxe2x80x2)rS(O)p(CHRxe2x80x2)rR16b, (CHRxe2x80x2)rS(O)2NR16aR16axe2x80x2, (CHRxe2x80x2)rNR16fS(O)2(CHRxe2x80x2)rR16b, C1-6 haloalkyl, C2-8 alkenyl substituted with 0-3 Rxe2x80x2, C2-8 alkynyl substituted with 0-3 Rxe2x80x2, and (CHRxe2x80x2)rphenyl substituted with 0-3 R16e;
R16a and R16axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R16e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R16e;
R16b, at each occurrence, is selected from C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)rC3-6 carbocyclic residue substituted with 0-3 R16e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R16e;
R16d, at each occurrence, is selected from C3-8 alkenyl, C3-8 alkynyl, methyl, CF3, C2-6 alkyl substituted with 0-3 R16e, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-3 R16e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R16e;
R16e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR16fR16f, and (CH2)rphenyl;
R16f, at each occurrence, is selected from H, C1-5 alkyl, and C3-6 cycloalkyl, and phenyl;
R17, at each occurrence, is independently selected from H and methyl;
Rxe2x80x2, at each occurrence, is selected from H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, (CH2)rC3-6 cycloalkyl, and (CH2)rphenyl substituted with R15e;
g is selected from 0, 1, 2, 3, and 4;
v is selected from 0, 1, and 2;
t is selected from 1 and 2;
w is selected from 0 and 1;
r is selected from 0, 1, 2, 3, 4, and 5;
q is selected from 1, 2, 3, 4, and 5; and
p is selected from 0, 1, and 2.
[2] In another embodiment, the present invention provides novel compounds of formula (I):
Z is selected from O, S, N(CN), and N(CONH2);
R2 is selected from H and C1-4 alkyl;
R6, at each occurrence, is selected from C1-4 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, (CF2)rCF3, CN, (CH2)rOH, (CH2)rOR6b, (CH2)rC(O)R6b, (CH2)rC(O)NR6aR6axe2x80x2, (CH2)rNR6dC(O)R6a, and (CH2)tphenyl substituted with 0-3 R6c;
R6a and R6axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R6c;
R6b, at each occurrence, is selected from C1-6 alkyl, C3-6 
cycloalkyl, and phenyl substituted with 0-3 R6c;
R6c, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, (CH2)rOH, (CH2)rSC1-5 alkyl, and (CH2)rNR6dR6d;
R6d, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
R13, at each occurrence, is selected from C1-4 alkyl, C3-6 cycloalkyl, (CH2)NR13aR13axe2x80x2, (CHRxe2x80x2)OH, (CH2)OR13b, (CH2)wC(O)R13b, (CH2)wC(O)NR13aR13axe2x80x2, (CH2)NR13dC(O)R13a, (CH2)wS(O)2NR13aR13axe2x80x2, (CH2)NR13dS(O)2R13b, and (CH2)w-phenyl substituted with 0-3 R13c;
R13a and R13axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R13c;
R13b, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R13c;
R13c, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, (CH2)rOH, and (CH2)rNR13dR13d;
R13d, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
v is selected from 0, 1 and 2;
q is selected from 1, 2, and 3; and
r is selected from 0, 1, 2, and 3.
[3] In another embodiment the present invention provides novel compounds of formula (I):
E is xe2x80x94(Cxe2x95x90O)xe2x80x94(CR9R10)vxe2x80x94(CR11R12)xe2x80x94, xe2x80x94(SO2)xe2x80x94(CR9R10)vxe2x80x94(CR11R12)xe2x80x94, 
R3 is selected from a (CH2)2N(CH3)2, (CR3xe2x80x2H)r-carbocyclic residue substituted with 0-5 R15, wherein the carbocyclic residue is selected from phenyl, C3-6 cycloalkyl, naphthyl, and adamantyl; and a (CR3xe2x80x2H)r-heterocyclic system substituted with 0-3 R15, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; and
R5 is selected from (CR5xe2x80x2H)t-phenyl substituted with 0-5 R16; and a (CR5xe2x80x2H)t-heterocyclic system substituted with 0-3 R16, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl.
[4] In another embodiment the present invention provides novel compounds of formula (I-i): 
R16, at each occurrence, is selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2)rNR16aR16axe2x80x2, NO2, CN, OH, (CH2)rOR16d, (CH2)rC(O)R16b, (CH2)rC(O)NR16aR16axe2x80x2, (CH2)rNR16fC(O)R16b, (CH2)rS(O)pR16b, (CH2)rS(O)2NR16aR16axe2x80x2, (CH2)rNR16fS(O)2R16b, and (CH2)rphenyl substituted with 0-3 R16e;
R16a and R16axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R16e;
R16b, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R16e;
R16d, at each occurrence, is selected from C1-6 alkyl and phenyl;
R16e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, OH, and (CH2)rOC1-5 alkyl; and
R16f, at each occurrence, is selected from H, and C1-5 alkyl.
[5] In another embodiment the present invention provides novel compounds of formula (I-ii): 
R16, at each occurrence, is selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2)rNR16aR16axe2x80x2, NO2, CN, OH, (CH2)rOR16d, (CH2)rC(O)R16b, (CH2)rC(O)NR16aR16axe2x80x2, (CH2)rNR16fC(O)R16b, (CH2)rS(O)pR16b, (CH2)rS(O)2NR16aR16axe2x80x2, (CH2)rNR16fS(O)2R16b, and (CH2)rphenyl substituted with 0-3 R16e;
R16a and R16axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R16e.
R16b at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R16e;
R16d, at each occurrence, is selected from C1-6 alkyl and phenyl;
R16e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, OH, and (CH2)rOC1-5 alkyl; and
R16f, at each occurrence, is selected from H, and C1-5 alkyl.
[6] In another embodiment the present invention provides novel compounds of formula (I-i):
R5 is CH2phenyl substituted with 0-3 R16;
E is xe2x80x94(Cxe2x95x90O)xe2x80x94(CR9R10)vxe2x80x94(CR11R12)xe2x80x94, or 
r is selected from 0, 1, and 2.
[7] In another embodiment the present invention provides novel compounds of formula (I-ii):
E is xe2x80x94(Cxe2x95x90O)xe2x80x94(CR9R10)vxe2x80x94(CR11R12)xe2x80x94, or 
R5 is CH2phenyl substituted with 0-3 R16; and
r is selected from 0, 1, and 2.
[8] In another embodiment the present invention provides novel compounds of formula (I-i):
J is selected from CH2 and CHR5;
K is selected from CH2 and CHR5;
L is selected from CH2 and CHR5;
R3 is a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-3 R15, wherein the carbocyclic residue is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl and adamantyl, and a (CR3xe2x80x2H)r-heterocyclic system substituted with 0-3 R15, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl.
[9] In another embodiment the present invention provides novel compounds of formula (I-ii):
K is selected from CH2 and CHR5;
L is selected from CH2 and CHR5; and
R3 is a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-3 R15, wherein the carbocyclic residue is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl and adamantyl, and a (CR3xe2x80x2H)r-heterocyclic system substituted with 0-3 R15, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl.
[10] In another embodiment the present invention provides novel compounds of formula (I):
M is absent or selected from CH2;
Q is CH2;
J is CH2;
K and L are independently selected from CH2 and CHR5;
Z is O, S, NCN, or NCONH2;
R1 is H;
R2 is H;
R3 is selected from a (CH2)rN(CH3)2, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-3 R15, wherein the carbocyclic residue is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl and adamantyl, and a (CR3xe2x80x2H)r-heterocyclic system substituted with 0-3 R15, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; and
R5 is selected from a CH2-phenyl substituted with 0-5 R16 and a CH2-heterocyclic system substituted with 0-3 R16, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl.
[11] In another embodiment, the present invention provides compounds of formula (II): 
or stereoisomers or pharmaceutically acceptable salts thereof, wherein:
J, K, and L are independently selected from CH2 and CHR5;
Z is selected from O, and N(CN);
E is xe2x80x94(Cxe2x95x90O)xe2x80x94(CR9R10)vxe2x80x94CR11R12xe2x80x94, or 
Ring A is cyclohexyl;
R3 is selected from CH2)rN(CH3)2, cyclopropyl, xe2x80x94CH2-cyclopropyl, phenyl substituted with 0-2 R15; and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15, wherein the heterocyclic system is selected from morpholinyl, pyridinyl, and thiazolyl;
R5 is selected from a xe2x80x94CH2-phenyl substituted with 0-2 R16;
R9 is selected from H, OH, N(CO)CH3, and NR9aR9axe2x80x2;
R9a and R9axe2x80x2, at each occurrence, are selected from H, methyl, ethyl, propyl, butyl, i-butyl;
alternatively, R9 and R10 join to form cyclohexyl;
R11 is selected from H, methyl, (CH2)rCONR11aR11axe2x80x2, C(O)OR11b, and a (CH2)-heterocyclic system, wherein the heterocyclic system is selected from morpholinyl and piperidinyl;
R11a and R11axe2x80x2 are independently selected from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl and t-butyl;
alternatively, R11a and R11axe2x80x2 along with the N to which they are attached, join to form a 5-6 membered heterocyclic system, wherein the heterocyclic system is selected from morpholinyl, piperidinyl, pyrrolidinyl, azapanyl, and N-methylpiperazinyl;
R11b is CH2-phenyl; R11g is selected from H, methyl, ethyl, propyl, i-propyl, C(O)OR11h, and SO2R11h;
R11h is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl and t-butyl;
R12 is H;
or alternatively, R11 and R12 join to form cyclopropyl, cyclopentyl, cyclohexyl, benzocyclopentyl, benzocyclohexyl, tetrahydropyan, tetrahydrofuran, or a 5-6-membered saturated heterocycle containing NR11g selected from pyrrolidine, and piperidine ring;
R15, at each occurrence, is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, pentyl, CF3, Cl, Br, I, F, NO2, CN, OH, OCH3, C(O)OR15bC(O)OH, C(O)CH3, C(O)NR15aR15axe2x80x2 and a 5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e, wherein the heterocyclic system is selected from triazolyl, imidazolyl, tetrazolyl, pyrazolyl, oxazolyl, and isoxazolyl;
R15a and R15axe2x80x2 are selected from hydrogen, methyl, ethyl, propyl, i-propyl, butyl, t-butyl, and a heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e, wherein the heterocyclic system is selected from morpholinyl;
R15b is selected from methyl and benzyl;
R15e is selected from methyl, ethyl and 2-cyanoethyl;
R16, at each occurrence, is selected from Cl, Br, I, and F,
v is 0 or 1; and
r is 0, 1, or 2.
[12] In another embodiment, the present invention provides compounds of formula (I), wherein the compound is selected from:
N-(3,5-diacetylphenyl)-Nxe2x80x2-[3-[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]-3-oxopropyl]-urea;
Nxe2x80x3-cyano-N-(3,5-diacetylphenyl)-Nxe2x80x2-[3-[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]-3-oxopropyl]-guanidine;
N-(3-acetylphenyl)-Nxe2x80x2-[(1S,2S)-2-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclohexyl ]-urea;
N-(3-acetylphenyl)-Nxe2x80x2-[(1R,2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclohexyl]-urea;
N-[(1R,2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclohexyl]-Nxe2x80x2-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-urea;
N-[(1R,2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclohexyl]-Nxe2x80x2-[4-(1-methyl-1H-tetrazol-5-yl)phenyl]-urea;
Nxe2x80x3-cyano-N-[(1R,2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclohexyl]-Nxe2x80x2-[4-(1-methyl-1H-tetrazol-5-yl)phenyl]-guanidine;
N-[(1R,2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclohexyl]-Nxe2x80x2-(4-pyridinyl)-urea;
N-[(1R,2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclohexyl]-Nxe2x80x2-[2-(4-morpholinyl)ethyl]-urea;
Nxe2x80x3-cyano-N-[(1R,2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclohexyl]-Nxe2x80x2-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-guanidine;
N-(5-acetyl-4-methyl-2-thiazolyl)-Nxe2x80x2-[(1R,2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclohexyl]-urea;
N-(3-acetylphenyl)-Nxe2x80x2-[1-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclohexyl]-urea;
N-[3,5-bis(1-methyl-1H-tetrazol-5-yl)phenyl]-Nxe2x80x2-[(1R,2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclohexyl]-urea;
N-[3,5-di(1H-imidazol-1-yl)phenyl]-Nxe2x80x2-[(1R,2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclohexyl]-urea;
N-[3,5-di(1H-1,2,4-triazol-1-yl)phenyl]-Nxe2x80x2-[(1R,2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclohexyl]-urea;
N-(3-acetylphenyl)-Nxe2x80x2-[1-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclopentyl]-urea;
N-(3-acetylphenyl)-Nxe2x80x2-[1-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclopropyl]-urea;
N-(3-acetylphenyl)-Nxe2x80x2-[2-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]-2,3-dihydro-1H-inden-2-yl-urea;
N-(3-acetylphenyl)-Nxe2x80x2-[2-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]-1,2,3,4-tetrahydro-2-naphthalenyl]-urea;
N-(5-acetyl-4-methyl-2-thiazolyl)-Nxe2x80x2-[1-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclopropyl]-urea;
N-(3-acetylphenyl)-Nxe2x80x2-[2-[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]-2-oxoethyl]-urea;
N-[3,5-bis(1-ethyl-1H-tetrazol-5-yl)phenyl]-Nxe2x80x2-[(1R,2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclohexyl]-urea;
N-[1-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclopropyl]-Nxe2x80x2-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-urea;
(alpha-1S,3S)-3-[(4-fluorophenyl)methyl]-alpha-[[[[3-(1-methyl-1H-tetrazol-5-yl)phenyl]amino]carbonyl]amino]-gamma-oxo-1-piperidinebutanoic acid, phenylmethyl ester;
(alpha-1S,3S)-3-[(4-fluorophenyl)methyl]-N-methyl-alpha-[[[[3-(1-methyl-1H-tetrazol-5-yl)phenyl]amino]carbonyl]amino]-gamma-oxo-1-piperidinebutanamide;
N-[(1S)-3-[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]-1-(4-morpholinylcarbonyl)-3-oxopropyl]-Nxe2x80x2-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-urea;
3-[[[[(1R,2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclohexyl]amino]carbonyl]amino]-benzoic acid, ethyl ester;
3-[[[[(1R,2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclohexyl]amino]carbonyl]amino]benzoic acid;
N-[1-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclopropyl]-Nxe2x80x2-[3-(4-morpholinylcarbonyl)phenyl]-urea;
N-[(1R,2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclohexyl]-Nxe2x80x2-[2-methoxy-5-(1-methyl-1H-tetrazol-5-yl)phenyl]-urea;
N-[3-[1-(2-cyanoethyl)-1H-tetrazol-5-yl]phenyl]-Nxe2x80x2-[(1R,2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclohexyl]-urea;
N-[(1R,2R)-2-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclohexyl]-Nxe2x80x2-[3-(1H-tetrazol-5-yl)phenyl]-urea;
3-[[[[1-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclopropyl]amino]carbonyl]amino]-4-methoxy-N-methyl-benzamide;
N-[1-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclopropyl]-Nxe2x80x2-[2-methoxy-5-(4-morpholinylcarbonyl)phenyl]-urea;
N-[(1S)-3-[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]-3-oxo-1-(1-pyrrolidinylcarbonyl)propyl]-Nxe2x80x2-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-urea;
-(alpha-1S,3S)-N-(1,1-dimethylethyl)-3-[(4-fluorophenyl)methyl]-alpha-[[[[3-(1-methyl-1H-tetrazol-5-yl)phenyl]amino]carbonyl]amino]-gamma-oxo-1-piperidinebutanamide,
N-[(1S)-3-[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]-3-oxo-1-(1-piperidinylcarbonyl)propyl]-Nxe2x80x2-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-urea;
N-(3-acetylphenyl)-Nxe2x80x2-[(2S)-2-amino-3-[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]-3-oxopropyl]-urea;
N-(3-acetylphenyl)-Nxe2x80x2-[(2R)-2-amino-3-[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]-3-oxopropyl]-urea;
3-[[[[1-[[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]carbonyl]cyclopropyl]amino]carbonyl]amino]-4-methoxybenzamide;
N-[(1S)-3-[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]-1-[(4-methyl-1-piperazinyl)carbonyl]-3-oxopropyl]-Nxe2x80x2-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-urea;
N-[(1S)-3-[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]-1-(4-morpholinylmethyl)-3-oxopropyl]-Nxe2x80x2-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-urea;
Nxe2x80x3-cyano-N-[(1S)-3-[(3S)-3-[(4-fluorophenyl)methyl]piperidinyl]-1-(4-morpholinylmethyl)-3-oxopropyl]-Nxe2x80x2-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-guanidine
3-[(4-fluorophenyl)methyl]-N,N-dimethyl-alpha-[[[[3-(1-methyl-1H-tetrazol-5-yl)phenyl]amino]carbonyl]amino]-gamma-oxo-(alpha-1S,3S)-1-piperidinebutanamide
N-{(1S)-1-({[(3-acetylanilino)carbonyl]amino}methyl)-2-[(3S)-3-(4-fluorobenzyl)piperidinyl]-2-oxoethyl}acetamide;
N-{(1R)-1-({[(3-acetylanilino)carbonyl]amino}methyl)-2-[(3S)-3-(4-fluorobenzyl)piperidinyl]-2-oxoethyl}acetamide;
3-[({[(1S)-3-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-1-(4-morpholinylmethyl)-3-oxopropyl]amino}carbonyl)amino]-N-methylbenzamide;
N-(3-chlorophenyl)-Nxe2x80x2-[(1S)-3-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-1-(4-morpholinylmethyl)-3-oxopropyl]urea;
N-(3-cyanophenyl)-Nxe2x80x2-[(1S)-3-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-1-(4-morpholinylmethyl)-3-oxopropyl]urea;
N-[(1S)-3-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-1-(4-morpholinylmethyl)-3-oxopropyl]-Nxe2x80x2-(3-methoxyphenyl)urea;
N-cyclopropyl-Nxe2x80x2-[(1S)-3-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-1-(4-morpholinylmethyl)-3-oxopropyl]urea
N-(cyclopropylmethyl)-Nxe2x80x2-[(1S)-3-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-1-(4-morpholinylmethyl)-3-oxopropyl]urea;
benzyl 3-[({[(1S)-3-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-1-(4-morpholinylmethyl)-3-oxopropyl]amino}carbonyl)amino]-4-methoxybenzoate;
N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-Nxe2x80x2-[(1S)-3-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-3-oxo-1-(1-piperidinylmethyl)propyl]urea;
N-[(1S,2R)-3-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-2-methyl-1-(4-morpholinylcarbonyl)-3-oxopropyl]-Nxe2x80x2-[3-(1-methyl-1H-tetraazol-5-yl)phenyl]urea;
3-[({[(1S,2R)-3-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-2-methyl-1-(4-morpholinylcarbonyl)-3-oxopropyl]amino}carbonyl)amino]-N-methylbenzamide;
N-(3,5-diacetylphenyl)-Nxe2x80x2-{(1R)-3-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-1-methyl-3-oxopropyl}urea;
N-{(1R)-3-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-1-methyl-3-oxopropyl}-Nxe2x80x2-[3-(1-methyl-1H-tetraazol-5-yl)phenyl]urea;
N-{(2S)-3-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-2-methyl-3-oxopropyl}-Nxe2x80x2-[3-(1-methyl-1H-tetraazol-5-yl)phenyl]urea;
N-(3-acetylphenyl)-Nxe2x80x2-{(1S)-1-{[tert-butyl(methyl)amino]methyl}-3-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-3-oxopropyl}urea;
N-{(2R)-3-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-2-methyl-3-oxopropyl}-Nxe2x80x2-[3-(1-methyl-1H-tetraazol-5-yl)phenyl]urea;
(2S)-N-cyclopropyl-4-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-2-[({[3-(1-methyl-1H-tetraazol-5-yl)phenthy]amino}carbonyl)amino]-4-oxobutanamide;
N-((1R)-2-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-1-{[({[3-(1-methyl-1H-tetraazol-5-yl)phenyl]amino}carbonyl)amino]methyl}-2-oxoethyl)acetamide;
N-[(1S)-3-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-1-(hexahydro-1H-azepin-1-ylcarbonyl)-3-oxopropyl]-Nxe2x80x2-[3-(1-methyl-1H-tetraazol-5-yl)phenyl]urea;
N-(1-{2-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-2-oxoethyl}cyclopropyl)-Nxe2x80x2-[3-(1-methyl-1H-tetraazol-5-yl)phenyl]urea;
N-((1R)-2-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-1-{[({[3-(1-methyl-1H-tetraazol-5-yl)phenyl]amino}carbonyl)amino]methyl}-2-oxoethyl)-2,2-dimethylpropanamide;
N-{(1R)-1-[({[(5-acetyl-4-methyl-1,3-thiazol-2-yl)amino]carbonyl}amino)methyl]-2-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-2-oxoethyl}-2,2-dimethylpropanamide;
N-{(1S)-1-{[tert-butyl(methyl)amino]methyl}-3-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-3-oxopropyl}-Nxe2x80x2-[3-(1-methyl-1H-tetraazol-5-yl)phenyl]urea;
N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-Nxe2x80x2-{(2R)-2-(diisobutylamino)-3-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-3-oxopropyl}urea;
N-{(2R)-2-(diisobutylamino)-3-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-3-oxopropyl}-Nxe2x80x2-[3-(1-methyl-1H-tetraazol-5-yl)phenyl]urea;
N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-Nxe2x80x2-{(1S)-1-{[tert-butyl(methyl)amino]methyl}-3-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-3-oxopropyl}urea;
N-{(1R)-3-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-1-methyl-3-oxopropyl}-Nxe2x80x2-(4-pyridinyl)urea;
N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)-Nxe2x80x2-{(1R,2R)-3-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-2-hydroxy-1-methyl-3-oxopropyl}urea;
N-(3,5-diacetylphenyl)-Nxe2x80x2-{(1R,2R)-3-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-2-hydroxy-1-methyl-3-oxopropyl}urea;
N-{3-[(dimethylamino)methyl]phenyl}-Nxe2x80x2-((1R,2R)-2-{[(3R)-3-(4-fluorobenzyl)-1-piperidinyl]carbonyl}cyclohexyl)urea;
3-({[(1-{[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]carbonyl}cyclopropyl)amino]carbonyl}amino)benzamide;
N-(1-{[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]carbonyl}cyclopropyl)-Nxe2x80x2-[2-methoxy-5-(1-methyl-1H-tetraazol-5-yl)phenyl]urea;
N-(1-{[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]carbonyl}cyclopropyl)-Nxe2x80x2-[3-(5-methyl-1H-tetraazol-1-yl)phenyl]urea;
N-{(1R)-2-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-1-methyl-2-oxoethyl}-Nxe2x80x2-[3-(1-methyl-1H-tetraazol-5-yl)phenyl]urea; and
N-(3,5-diacetylphenyl)-Nxe2x80x2-{(1S)-2-[(3S)-3-(4-fluorobenzyl)-1-piperidinyl]-1-methyl-2-oxoethyl}urea.
In another embodiment, the present invention provides a pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the present invention.
In another embodiment, the present invention provides a method for modulation of chemokine receptor activity comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention.
In another embodiment, the present invention provides a method for treating inflammatory disorders comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention
In another embodiment, the present invention provides a method for treating or preventing disorders selected from asthma, allergic rhinitis, atopic dermatitis, inflammatory bowel diseases, idiopathic pulmonary fibrosis, bullous pemphigoid, helminthic parasitic infections, allergic colitis, eczema, conjunctivitis, transplantation, familial eosinophilia, eosinophilic cellulitis, eosinophilic pneumonias, eosinophilic fasciitis, eosinophilic gastroenteritis, drug induced eosinophilia, HIV infection, cystic fibrosis, Churg-Strauss syndrome, lymphoma, Hodgkin""s disease, and colonic carcinoma.
In another embodiment, the compound of Formula (I) is 
In another embodiment, the compound of Formula (I) is 
In another embodiment, J is CH2, K is selected from CH2 and CHR5, and L is selected from CH2 and CHR5, wherein at least one of K or L contains an R5.
In another embodiment, K is selected from CHR5 and L is CH2.
In another embodiment, L is selected from CHR5 and K is CH2.
In another embodiment, E is xe2x80x94(Cxe2x95x90O)xe2x80x94(CR9R10)vxe2x80x94(CR11R12)xe2x80x94, 
In another embodiment E is xe2x80x94(Cxe2x95x90O)xe2x80x94(CR9R10)vxe2x80x94(CR11R12)xe2x80x94, 
In another embodiment E is xe2x80x94(Cxe2x95x90O)xe2x80x94(CR9R10)vxe2x80x94(CR11R12)xe2x80x94, xe2x80x94(SO2)xe2x80x94(CR9R10)vxe2x80x94(CR11R12)xe2x80x94, 
In another embodiment, E is xe2x80x94(Cxe2x95x90O)xe2x80x94(CR9R10)vxe2x80x94(CR11R12).
In another embodiment, E is 
In another embodiment, Z is selected from O and N(CN).
In another embodiment, Ring A is cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, or phenyl.
In another embodiment, Ring A is cyclohexyl.
In another embodiment, R2 is H.
In another embodiment, R3 is selected from a (CR3xe2x80x2R3xe2x80x3)rxe2x80x94C3-8 carbocyclic residue substituted with 0-5 R15; a (CR3xe2x80x2R3xe2x80x3)rxe2x80x94C9-10 carbocyclic residue substituted with 0-4 R15; and a (CR3xe2x80x2R3xe2x80x3)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R15.
In another embodiment, R3 is selected from (CH2)rN(CH3)2.
In another embodiment, R3 is selected from a (CR3xe2x80x2H)r-carbocyclic residue substituted with 0-5 R15, wherein the carbocyclic residue is selected from phenyl, (CH2)xe2x80x94C3-6 cycloalkyl, naphthyl, and adamantyl; and a (CR3xe2x80x2H)r-heterocyclic system substituted with 0-3 R15, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl.
In another embodiment, R3 is selected from a phenyl substituted with 0-2 R15; and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15, wherein the heterocyclic system is selected from pyridinyl, thiazolyl, and r is 0 or 1.
In another embodiment, R5 is selected from (CR5xe2x80x2H)t-phenyl substituted with 0-5 R16; and a (CR5xe2x80x2H)t-heterocyclic system substituted with 0-3 R16, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl.
In another embodiment, R5 is selected from a CH2xe2x80x94C3-10 carbocyclic residue substituted with 1-5 R16 and a CH2-heterocyclic system substituted with 0-3 R15, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl.
In another embodiment, R5 is CH2-phenyl substituted with 0-3 R16.
In another embodiment, R11 and R12 join to form cyclopropyl, cyclopentyl, cyclohexyl, benzocyclopentyl, benzocyclohexyl, tetrahydropyan, and tetrahydrofuran, or a 5-6-membered saturated heterocycle containing NR11g pyrrolidine, and piperidine ring.
In another embodiment, v is 0.
It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment to describe additional even more preferred embodiments of the present invention. Furthermore, any elements of an embodiment are meant to be combined with any and all other elements from any of the embodiments to describe additional embodiments.
The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, Cxe2x95x90N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
The term xe2x80x9csubstituted,xe2x80x9d as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced.
When any variable (e.g., Ra) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 Ra, then said group may optionally be substituted with up to two Ra groups and Ra at each occurrence is selected independently from the definition of Ra. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, xe2x80x9cC1-8 alkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, examples of which include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl. C1-8 alkyl, is intended to include C1, C2, C3, C4, C5, C6, C7, and C8 alkyl groups. xe2x80x9cAlkenylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like. xe2x80x9cAlkynylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl, and the like. xe2x80x9cC3-6 cycloalkylxe2x80x9d is intended to include saturated ring groups having the specified number of carbon atoms in the ring, including mono-, bi-, or poly-cyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl in the case of C7 cycloalkyl. C3-6 cycloalkyl, is intended to include C3, C4, C5, and C6 cycloalkyl groups.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo, and iodo; and xe2x80x9chaloalkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups, for example CF3, having the specified number of carbon atoms, substituted with 1 or more halogen (for example xe2x80x94CvFw where v=1 to 3 and w=1 to (2v+1)).
As used herein, the term xe2x80x9c5-6-membered cyclic ketalxe2x80x9d is intended to mean 2,2-disubstituted 1,3-dioxolane or 2,2-disubstituted 1,3-dioxane and their derivatives.
As used herein, xe2x80x9ccarbocyclexe2x80x9d or xe2x80x9ccarbocyclic residuexe2x80x9d is intended to mean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl; [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
As used herein, the term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclic systemxe2x80x9d is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic ring which is saturated, partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, NH, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. As used herein, the term xe2x80x9caromatic heterocyclic systemxe2x80x9d is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heterotams independently selected from the group consisting of N, O and S.
Examples of heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, xcex2-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, and xanthenyl. Preferred heterocycles include, but are not limited to, pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiaphenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, isoidolyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc . . . ) the compounds of the present invention may be delivered in prodrug form. Thus, the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same. xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carriers which release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.
xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The compounds of Formula I can be prepared using the reactions and techniques described below. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention. It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991).
Generally, compounds described in the scope of this patent application can be synthesized by the route described in Scheme 1. Note that only one substitution pattern has been drawn for demonstration purposes, but more substitutents on the pyrrolidine or piperidine ring can be present as stipulated in the scope of this application. Thus, the appropriately substituted pyrrolidine (n=0) or piperidine (n=1) 1 is acylated or sulfonated by a N-protected acid chloride or sulfonylchloride 2, (X=Cl and where E represents a linkage described within the scope of this application in its fully elaborated form with the appropriate protecting groups as understood by one skilled in the art or in a precursor form which can be later elaborated into its final form by methods familiar to one skilled in the art) in the presence of base or an acid scavenger to yield the piperidinyl- or pyrrolidinylcarbonyl or piperidinyl- or pyrrolidinylsulfonyl protected amines 3. The coupling can be performed at xe2x88x9278xc2x0 C. to room temperature to the reflux temperature of the solvent. Aqueous base such as NaOH, KOH, etc. may be employed under Schotten-Baumann conditions. Amine bases can also be employed such as Huenig""s base or triethylamine in an inert solvent. Acid scavengers can also be employed such as but not limited to K2CO3, Na2CO3, etc. Coupling can also be done via the free carboxylic acid and the pyrrolidine/piperidine base by a variety of methods familiar to one skilled in the art. Some of the coupling reagents include but are not limited to DCC (dicyclohexylcarbodiimide), EDC (N-ethyl, Nxe2x80x2-dimethylaminopropylcarbodiimide), BOP (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate), PyBOP (Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate), HATU (O-(7-Azabenzotriazol-1-yl)-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium hexafluorophosphate), TBTU (O-(Benzotriazol-1-yl)-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium tetrafluoroborate), etc., in an inert solvent such as DMF, THF, methylene chloride, etc. The non-diimide coupling reagents also might require the presence of a base such as triethylamine, Huenig""s base, etc. The protecting group is subsequently removed to yield amine 4. Protecting groups include phthalimide which can be removed by hydrazine, a reaction familiar to one skilled in the art; bis-BOC which can be removed by either TFA or HCl dissolved in a suitable solvent, both procedures being familiar to one skilled in the art; a nitro group instead of an amine which can be reduced to yield an amine by conditions familiar to one skilled in the art; 2,4-dimethyl pyrrole (S. P. Breukelman, et al. J. Chem. Soc. Perkin Trans. I, 1984, 2801); N-1,1,4,4-Tetramethyl-disilylazacyclopentane (STABASE) (S. Djuric, J. Venit, and P. Magnus Tet. Lett 1981, 22, 1787) and other protecting groups. Reaction with an isocyanate or isothiocyanate 5 (Zxe2x95x90O,S) yields urea or thiourea 6. Reaction with a chloroformate or chlorothioformate 7 (Zxe2x95x90O,S) such as o-, p-nitrophenyl-chloroformate or phenylchloroformate (or their thiocarbonyl equivalents), followed by diplacement with an amine 9, also yields the corresponding urea or thiourea 6. Likewise, reaction of carbamate 8 (Yxe2x95x90H, or 2- or 4-NO2) with disubstituted amine 10 yields trisubstituted urea or thiourea 12. Reaction of the amine 4 with an N,N-disubstituted carbamoyl chloride 11 (or its thiocarbonyl equivalent) yields the corresponding N,N-disubstituted urea or thiourea 12. Amine 4 can also be reductively aminated to yield 13 by conditions familiar to one skilled in the art and by the following conditions: Abdel-Magid, A. F., et al. Tet. Lett. 1990, 31, (39) 5595-5598. This secondary amine can subsequently be reacted with isocyanates or isothiocyanates to yield trisubstituted ureas 14 or with carbamoyl chlorides to yield tetrasubstituted ureas 15. 
One can also convert amine 4 or 13 into an isocyanate, isothiocyanate, carbamoyl chloride or its thiocarbonyl equivalent (isocyanate: Nowakowski, J. J Prakt. Chem/Chem-Ztg 1996, 338 (7), 667-671; Knoelker, H.-J. et al., Angew. Chem. 1995, 107 (22), 2746-2749; Nowick, J. S. et al., J. Org. Chem. 1996, 61 (11), 3929-3934; Staab, H. A.; Benz, W.; Angew Chem 1961, 73; isothiocyanate: Strekowski L. et al., J. Heterocycl. Chem. 1996, 33 (6), 1685-1688; Kutschy, Pet al., Synlett. 1997, (3), 289-290) carbamoyl chloride: Hintze, F.; Hoppe, D.; Synthesis (1992) 12, 1216-1218; thiocarbamoyl chloride: Ried, W.; Hillenbrand, H.; Oertel, G.; Justus Liebigs Ann Chem 1954, 590) (these reactions are not shown in Scheme 1). These isocyanates, isothiocyantes, carbamoyl chlorides or thiocarbamoyl chlorides can then be reacted with R2R3NH to yield di- or trisubstituted ureas or thioureas 12. An additional urea forming reaction involves the reaction of carbonyldiimidazole (CDI) (Romine, J. L.; Martin, S. W.; Meanwell, N. A.; Epperson, J. R.; Synthesis 1994 (8), 846-850) with 4 followed by reaction of the intermediate imidazolide with 9 or in the reversed sequence (9+CDI, followed by 4). Activation of imidazolide intermediates also facilitates urea formation (Bailey, R. A., et al., Tet. Lett. 1998, 39, 6267-6270). One can also use 13 and 10 with CDI. The urea forming reactions are done in an aprotic inert solvent such as THF, toluene, DMF, etc., at room temperature to the reflux temperature of the solvent and can employ the use of an acid scavenger or base when necessary such as carbonate and bicarbonate salts, triethylamine, DBU, Huenig""s base, DMAP, etc. One can also make ureas (or thioureas) using the phenylcarbamates (or thiocarbamates) of amine R2R3NH, namely R2R3Nxe2x80x94(Cxe2x95x90O)xe2x80x94OPh (or R2R3Nxe2x80x94(Cxe2x95x90S)xe2x80x94OPh) (and substituted phenylcarbamates such as nitrophenylcarbamates), and reacting them with 4 or 13 to yield urea or thiourea 15 (this procedure is not shown in Scheme 1 but is similar in concept to 4 being converted to the carbamate 8 and then to the urea 6.
Substituted pyrrolidines and piperidines 1 can either be obtained commercially or be prepared as shown in Scheme 2. Commercially available N-benzylpiperid-3-one 16 can be debenzylated and protected with a BOC group employing reactions familiar to one skilled in the art. Subsequent Wittig reaction followed by reduction and deprotection yields piperidine 20 employing reactions familiar to one skilled in the art. Substituted pyrrolidines may be made by a similar reaction sequence. Other isomers and analogs around the piperidine ring can also be made by a similar reaction sequence. Chiral pyrrolidines/piperidines can be synthesized via asymmetric hydrogenation of 18 using chiral catalysts (see Parshall, G. W. Homogeneous Catalysis, John Wiley and Sons, New York: 1980, pp. 43-45; Collman, J. P., Hegedus, L. S. Principles and Applications of Organotransition Metal Chemistry, University Science Books, Mill Valley, Calif., 1980, pp. 341-348). 
The cyanoguanidines (Zxe2x95x90Nxe2x80x94CN) can be synthesized by the method of K. S. Atwal, et al. and references contained therein (J. Med. Chem. (1998) 41, 217-275). The nitroethylene analog (Zxe2x95x90Cxe2x80x94NO2) can be synthesized by the method of F. Moimas, et al. (Synthesis 1985, 509-510) and references contained therein. The malononitrile analog (Zxe2x95x90C(CN)2) may be synthesized by the method of S. Sasho, et al. (J. Med. Chem. 1993, 36, 572-579).
Guanidines (Zxe2x95x90NR1a) can be synthesized by the methods outlined in Scheme 3. Compound 21 where Zxe2x95x90S can be methylated to yield the methylisothiourea 22. Displacement of the SMe group with amines yields substituted guanidines 23 (see H. King and I. M. Tonkin J. Chem. Soc. 1946, 1063 and references therein). Alternatively, reaction of thiourea 21 with amines in the presence of triethanolamine and xe2x80x9clac sulfurxe2x80x9d which facilitates the removal of H2S yields substituted guanidines 23 (K. Ramadas, Tet. Lett. 1996, 37, 5161 and references therein). Finally, the use of carbonimidoyldichloride 24, or 25 followed by sequential displacements by amines yields the corresponding substituted guanidine 23 (S. Nagarajan, et al., Syn. Comm. 1992, 22, 1191-8 and references therein). In a similar manner, carbonimidoyldichlorides, R2xe2x80x94Nxe2x95x90C(Cl)2 (not shown in Scheme 3) and R3xe2x80x94Nxe2x95x90C(Cl)2 (not shown) can also be reacted sequentially with amines to yield di- and trisubstituted guanidine 23. 
Multisubstituted pyrrolidines and piperidines may be synthesized by the methods outlined in Scheme 4. Monoalkylation of 26 via an enolate using LDA or potassium hexamethyldisilazane, or converting 26 first to an enamine, or by using other bases, all of which can be done in THF, ether, dioxane, benzene, or an appropriate an aprotic solvent at xe2x88x9278xc2x0 C. to room temperature with an alkylating agent such as methyl iodide, benzyl bromide, etc. where X is leaving group such as Cl, Br, I, OTs, OMs, triflate, etc., yields product 27. This product can subsequently undergo alkylation again under thermodynamic or kinetic conditions and afterwards, if need be, can undergo two more alkylations to produce tri- and tetrasubstituted analogs of 27. The thermodynamic or kinetic conditions yield regioselectively alkylated products (for a discussion on thermodynamic vs. kinetic alkylations see H. House Modern Synthetic Reactions, W. A. Benjamin, Inc. (Menlo Park, Calif.: 1972) chapter 9). 
Subsequent Wittig olefination yields compound 28. Hydrogenation (asymmetric hydrogenation is an option here: Parshall, G. W. Homogeneous Catalysis, John Wiley and Sons, New York: 1980, pp. 43-45; Collman, J. P., Hegedus, L. S. Principles and Applications of Organotransition Metal Chemistry, University Science Books, Mill Valley, Calif., 1980, pp. 341-348) yields pyrrolidine or piperidine 29 which can be resolved into its relative and/or absolute isomers at this stage or later on in the synthesis either by crystallization, chromatographic techniques, or other methods familiar to one skilled in the art. The amine 29 an then be elaborated into the compounds of this invention by methods discussed previously (Scheme 1). The carbonyl-containing intermediate 27 in Scheme 4 can also be reduced to the methylene analog via a Wolff-Kishner reduction and modifications thereof, or by other methods familiar to one skilled in the art. The carbonyl group can also be reduced to an OH group, which can undergo displacement reactions familiar to one skilled in the art to synthesize the R6 groups. This piperidine or pyrrolidine can be deprotected and elaborated to the compounds of this invention by methods discussed earlier. Thus, mono-, di-, tri-, or tetraalkylated carbonyl-containing pyrrolidines or piperidines can be synthesized, which in turn can be reduced to the corresponding xe2x80x94CH2xe2x80x94 analogs employing the Wolff-Kishner reduction or other methods. 
Another method for synthesizing gem-substituted pyrrolidines and piperidines is shown in Scheme 5. It is understood by one skilled in the art that some of the steps in this scheme can be rearranged. It is also understood that gem-disubstitution is only shown at only one position on the piperidine ring and that similar transformations may
be performed on other carbon atoms as well, both for piperidine and pyrrolidine. Thus, 3-carboethoxypiperidine 30 may be BOC-protected and alkylated employing a base such as LDA, KHMDS, LHDMS, etc., in THF, ether, dioxane, etc. at xe2x88x9278xc2x0 C. to room temperature, and an alkylating agent R6X where X is a halide (halide=Cl, Br, I), mesylate, tosylate or triflate, to yield 32. Reduction using DIBAL, for example, and if necessary followed by oxidation such as a Swern oxidation (S. L. Huang, K. Omura, D. Swern J. Org. Chem. 1976, 41, 3329-32) yields aldehyde 33. Wittig olefination (34) followed by deprotection yields 35 which may be elaborated as described previously into the compounds of this invention. Reduction of the Wittig adduct 34 yields 36 which may be deprotected to yield 37 which may be in turn elaborated as described previously into the compounds of this invention. Reaction of aldehyde 33 with an alkyllithium or Grignard reagent yields alcohol 38 which may be reduced catalytically or with Et3SiH/TFA (J. Org. Chem. 1969, 34, 4; J. Org. Chem. 1987, 52, 2226) if R5*(R5*=R5 or a precursor thereof) is aromatic to yield 39. If R5* is not aromatic, then the OH may be reduced by the method of Barton (Barton, D. H. R.; Jaszberenyi, J. C. Tet. Lett. 1989, 30, 2619 and other references therein). Once tosylated, the alcohol can also be displaced with dialkyllithium cuprates (not shown) (Hanessian, S.; Thavonekham, B.; DeHoff, B.; J Org. Chem. 1989, 54, 5831). Deprotection if necessary yields 40 which may be elaborated as described previously into the compounds of this invention. 
A method for the alkylation of alkyl groups, arylalkyl groups, allylic groups, propargylic groups, etc., and a variety of other electrophiles onto the pyrrolidinyl and/or piperidinyl alpha-carbons (alpha to the ring nitrogen atom) is represented by the work of Peter Beak, et al. as shown in Scheme 6. It is understood by one skilled in the art that the R5 and R13 groups are either in their precursor, protected, or final form. Only one R5 group is shown to be substituted on piperidine/pyrrolidine 41. However it is understood by one skilled in the art that additional functionality may be present on the ring in either precursor, protected, or final form. Thus lithiation with an alkyllithium reagent such as n-BuLi or s-BuLi as shown, followed by quenching with an electrophilic species such as R5X or R13X where X is a leaving group such as Cl, Br, I, OMs, OTs, triflate, etc., and R5 and R13 are in their precursor, protected, or final form, yields monoalkylated piperidine/pyrrolidine 42. This alkylation may occur either stereoselectively (P. Beak and W. K. Lee J. Org. Chem. 1990, 55, 2578-2580) or enantioselectively if sparteine is included as a source of chirality (P. Beak, et al., J. Am. Chem. Soc. 1994, 116, 3231-3239). The alkylation process may be repeated up to three more times as shown in Scheme 6 to result in di-, tri-, and tetrasubstitution at the alpha-positions.
Compounds where R9 and R10 form a cyclic 3,4,5,6, or 7-membered ring can be synthesized by the methods disclosed in Scheme 7. These same methods may also be used to synthesize gem-disubstituted compounds in which R9 can be different from R10 by step-wise alkylation of the malonate derivative. Of course, this scheme may be used to synthesize compounds where R10xe2x95x90H and R9xe2x95x90R10 also. For example, a cyclohexyl-fused malonate may be synthesized by Michael addition and alkylation of I(CH2)4CHxe2x95x90CCO2Me with dimethyl malonate employing NaH/DMF (Desmaele, D.; Louvet, J.-M.; Tet Lett 1994, 35 (16), 2549-2552) or by a double Michael addition (Reddy, D. B., et al., Org. Prep. Proced. Int. 24 (1992) 1, 21-26) (Downes, A. M.; Gill, N. S.; Lions, F.; J Am Chem or by an alkylation followed by a second intromolecular alkylation employing an iodoaldehyde (Suami, T.; Tadano, K.; Kameda, Y.; Iimura, Y.; Chem Lett 1984, 1919), or by an alkylation followed by a second intramolecular alkylation employing an alkyl dihalide (Kohnz, H.; Dull, B.; Mullen, K.; Angew Chem 1989, 101 (10), 1375), etc. 
Subsequent monosaponification (Pallai, P. V., Richman, S., Struthers, R. S., Goodman, M. Int. J. Peptide Protein Res. 1983, 21, 84-92; M. Goodman Int. J. Peptide Protein Res. 19831, 17, 72-88), standard coupling with pyrrolidine/piperidine 1 yields 48. Reduction with LiBH4 yields 49 which can be then converted to amine 50 and then to the compounds of this invention by procedures as discussed previously or by other procedures which are familiar to one skilled in the art. Alcohol 49 can also be converted to an aldehyde which would allow the introduction of substituents R11 and R12 by methods familiar to one skilled in the art. Alcohol 49 can also be displaced via its tosylate, mesylate, or triflate with cyanide ion to form a nitrile. This nitrile can optionally be mono or bisalkylated at the alpha carbon and then be reduced to an amine to yield an analog of 50 with an extra carbon atom. The nitrile can also be hydrolyzed to a carboxylic acid which can be converted to an amine via Curtius rearrangement followed by hydrolysis to result in 50 with no substitution or mono- or disubstitution at the alpha carbon atom. Ester 48 can be hydrolyzed to a carboxylic acid. Curtius rearrangement followed by hydrolysis yields 50 where there is one less carbon atom. All of these generated amines can be reacted as in Scheme 1 to yield compounds of this invention.
Scheme 8 describes another method for the synthesis of compounds where R9 and R10 are taken together to form cycloalkyl groups. Aminoalcohols 52 are found in the literature (CAS Registry Nos. for n=0,1,2,3, respectively: 45434-02-4, 2041-56-7, 2239-31-8, 2041-57-8). They can easily be protected, as with a BOC group (or CBZ, or any other compatible protecting group) by known procedures familiar to one skilled in the art to yield alcohols 53. The alcohols can then be oxidized by methods familiar to one skilled in the art and activated for coupling as described previously and coupled to pyrrolidine/piperidine 1 by the conditions described in Scheme 1 to yield 55. Subsequent deprotection yields amine 56 which can be elaborated to the compounds of this invention as described previously. 
A method to introduce cycloalkyl groups at R11R12 is shown in Scheme 9. Protection of the nitrogen of compounds 57 which are commercially available yields 58 (the protecting group may be BOC, CBZ, or any other compatible protecting group) by procedures familiar to one skilled in the art. These can be then coupled as discussed previously to 1 and deprotected and elaborated to the compounds of this invention. Esterification by any one of a number procedures familiar to one skilled in the art (for example A. Hassner and V. Alexanian, Tet. Lett, 1978, 46, 4475-8) followed by reduction with DIBAL (or alternatively reduction to the alcohol with, for example, LiBH4, followed by Swern oxidation (op. cit.) yields aldehyde 59. One carbon homologation via the Wittig reaction followed by hydrolysis of the vinyl ether yields aldehyde 61. Oxidation followed by standard coupling to 1 yields 62 followed by deprotection yields amine 63 which can be elaborated to the compounds of this invention by the methods previously discussed. 
Aminoalkylsulfonyl chlorides may be synthesized by the methods described in Scheme 10. Protected alcohol 64 is converted into the acetylthio derivative 65 via Sn2 displacement chemistry familiar to one skilled in the art. For instance, 64 can be converted into a tosylate, mesylate, triflate, etc., and displaced with KSAc in a suitable solvent such as an alcohol, DMF, DMSO, etc. Another alternative is the Mitsunobu reaction. Alternatively, the acetylthio group may be added to a double bond via radical chemistry (Abbenante, G.; Prager, R. H. Aust. J. Chem. 1992, 45, 1801-1810). Conversion of 65 into sulfonylchloride 66 may be achieved using chlorine gas and water in an inert solvent such as for example, methylene chloride (Abbenante, G.; Prager, R. H. Aust. J. Chem. 1992, 45, 1801-1810). Coupling (67) and deprotection (68) and formation of the urea or urea isostere on the right hand side as discussed previously in Scheme 1 and elsewhere in this application yields compounds of this invention. 
A method for the synthesis of N-substituted heterocycles at R5 is shown in Scheme 11. The heterocycle can be deprotonated with NaH or by other bases familiar to one skilled in the art, in a solvent such as DMF, THF, or another appropriate aprotic solvent and reacted with piperidine or pyrrolidine 69 at room temperature to the reflux temperature of the solvent. Deprotection and elaboration as described before yields compounds where R5 contains an N-substituted heterocycle. If the nitrogen atom of the heterocycle is sufficiently nucleophilic, then an acid scavenger, such as K2CO3, KHCO3, Na2CO3, NaHCO3, amongst others, can be used in place of NaH, employing THF, DMF, or methyl ethyl ketone as solvents. In this case hydroxylic solvents may be used as well, such as methanol, ethanol, etc. from room temperature to the reflux temperature of the solvent. Compound 69 as well as its other positional isomers are available, for example, from commercially available 4-hydroxymethylpiperidine, 2-, 3- and 4-carboethoxypiperidine, L- or D-proline ethyl ester, or from methyl 1-benzyl-5-oxo-3-pyrrolidinecarboxylate by methods familiar to one skilled in the art and as discussed previously in this application. 
A method for the synthesis of C-substituted heterocycles at R5 is shown in Scheme 12. Many heterocycles such as the ones shown in Scheme 12, but not limited thereto, can be metallated with strong bases such as LDA, n-BuLi, sec-BuLi, t-BuLi, etc. to yield the corresponding anionic species. These anions may also be generated via halogen-metal exchange employing n-BuLi, or other alkyllithium reagents. These reactions may be performed in THF, ether, dioxane, DME, benzene, etc. at xe2x88x9278xc2x0 C. to room temperature. 
For reviews of these metallations and halogen-metal exchange reactions see Organometallics in Organic Synthesis, FMC Corp., Lithium Division, 1993, pp. 17-39; Lithium Link, FMC Corp., Spring 1993, pp. 2-17; n-Butyllithium in Organic Synthesis, Lithium Corp. of America, 1982, pp. 8-16; G. Heinisch, T. Langer, P. Lukavsky, J. Het. Chem. 1997, 34, 17-19. The anions can then be quenched with electrophile 69 or its positional isomers to yield the corresponding C-alkylated heterocyclic pyrrolidine or piperidine 71. 
Another method for the synthesis of C-substituted heterocyclic-methylpyrrolidines or piperidines is shown in Scheme 13. The protected aldehyde 72 is reacted with the anion of the heterocycle (its generation as described previously) at xe2x88x9278xc2x0 C. to room temperature with or without CeCl3 in an inert solvent such as THF, ether, dioxane, DME, benzene, etc. to yield carbinol 73. Catalytic hydrogenation of the alcohol yields the corresponding methylene compound 71. Other reduction methods include Et3SiH/TFA (J. Org. Chem. 1969, 34, 4; J. Org. Chem. 1987, 52, 2226) amongst others familiar to one skilled in the art. It is understood by one skilled in the art that the aldehyde group can be located in other positions instead of, for example, the 4-position of piperidine in compound 72 as depicted in Scheme 13. It is to be understood that other heterocycles may also be used besides the ones shown in Scheme 12 and 13.
The anions of the methyl-substituted heterocycles may also be reacted with a BOC-protected piperidone or pyrrolidone (74) to yield alcohols 75 as shown in Scheme 14 (see above reviews on metallations for references). The OH may be reduced by the method of Barton (Barton, D. H. R.; Jaszberenyi, J. C. Tet. Lett. 1989, 30, 2619 and other references therein) to yield piperidines and pyrrolidines 76. These can subsequently be taken on to the compounds of this invention as described previously. It is understood by one skilled in the art that the carbonyl group can be located in other positions instead of, for example, the 4-position of piperidine in compound 74 as depicted in Scheme 14. It is to be understood that other heterocycles may also be used besides the ones shown in Scheme 14. 
One may also react aryl (phenyl, naphthyl, etc.) anions, generated either by halogen-metal exchange or by ortho-directed metallation (Snieckus, V. Chem. Rev. 1990, 90, 879-933) using n- or s- or t-BuLi in an aprotic solvent such as THF, ether, etc., with or without TMEDA and allow them to react with compounds 69, 72, and 74 with subsequent elaboration to yield the compounds of this invention by t he methods depicted in Schemes 11-14.
Another method for the preparation of C-substituted heterocycles is shown in Scheme 15. Protected piperidone 74 undergoes a Wittig reaction with heterocyclic phosphorous ylides to yield 77. Hydrogenation over a noble metal catalyst such as Pd in an alcoholic solvent or with an optically active transition metal catalyst (see asymmetric hydrogenation references of Parshall and Coleman, op. cit.) yields 76 which can be further elaborated into the compounds of this invention by the procedures described previously. It will be appreciated by one skilled in the art that the carbonyl group can be located in other positions instead of, for example, the 4-position of piperidine in compound 74 as depicted in Scheme 15. It is to be understood that other heterocycles may also be used besides the ones shown in Scheme 15. 
Syntheses of amines 9, 10, and the amines which are precursors to isocyanates, isothiocyanates 5 or of phenylcarbamates or thiocarbamates, all of which have been discussed in regards to Scheme 1, will now be discussed. For example, 3-nitrobenzeneboronic acid (79: Scheme 16) is commerically available and can undergo Suzuki couplings (Suzuki, A. Pure Appl. Chem. 1991, 63, 419) with a wide variety of substituted iodo- or bromo aryls (aryls such as phenyl, naphthalene, etc.), heterocycles, alkyls, akenyls (Moreno-manas, M., et al., J. Org. Chem., 1995, 60, 2396), or alkynes. It can also undergo coupling with triflates of aryls, heterocycles, etc. (Fu, J.-m, Snieckus, V. Tet. Lett. 1990, 31, 1665-1668). Both of the above reactions can also undergo carbonyl insertion in the presence of an atmosphere of carbon monoxide (Ishiyama, et al., Tet. Lett. 1993, 34, 7595). These nitro-containing compounds (81 and 83) can then be reduced to the corresponding amines either via catalytic hydrogenation, or via a number of chemical methods such as Zn/CaCl2 (Sawicki, E. J Org Chem 1956, 21). The carbonyl insertion compounds (84) can also undergo reduction of the carbonyl group to either the CHOH or CH2 linkages by methods already discussed (NaBH4 or Et3SiH, TFA, etc.). These amines can then be converted to isocyanate 5 via the following methods (Nowakowski, J. J Prakt Chem/Chem-Ztg 1996, 338 (7), 667-671; Knoelker, H.-J. et al., Angew Chem 1995, 107 (22), 2746-2749; Nowick, J. S. et al., J Org Chem 1996, 61 (11), 3929-3934; Staab, H. A.; Benz, W.; Angew Chem 1961, 73); to isothiocyanate 5 via the following methods (Strekowski L. et al., J Heterocycl Chem 1996, 33 (6), 1685-1688; Kutschy, Pet al., Synlett 1997, (3), 289-290); to carbamoyl chloride 11 (after 82 or 84 is reductively aminated with an R2 group) (Hintze, F.; Hoppe, D.; Synthesis (1992) 12, 1216-1218); to thiocarbamoyl chloride 11 (after 82 or 84 is reductively aminated with an R2 group) (Ried, W.; Hillenbrand, H.; Oertel, G.; Justus Liebigs Ann Chem 1954, 590); or just used as 9, or 10 (after 82 or 84 is reductively aminated with an R2 group), in synthesizing the compounds of this invention by the methods depicted in Scheme 1.
Nitrobenzoic acids are precursors to N-monosubstituted nitrobenzamides which can be converted to tetrazoles by the method of Duncia, J. V. et al., J. Org. Chem., 1991, 56, 2395-2400, or by the method of Thomas, E., Synthesis (1993) 767-768 (and other methods familiar to one skilled in the art). These tetrazole-containing nitrobenzenes can be reduced to the corresponding anilines and coupled to make ureas and urea isosteres (i.e., Z is not oxygen in formula I) as in the discussion surrounding Scheme 1 to make compounds of the present invention. As in the above synthesis of tetrazole-substituted anilines, one can also make other heterocycle-substituted anilines in a similar de novo fashion using reactions familiar to one skilled in the art. 
Likewise, protected aminobromobenzenes or triflates or protected aminobromoheterocycles or triflates 85 (Scheme 17) may undergo Suzuki-type couplings with arylboronic acids or heterocyclic boronic acids (86). These same bromides or triflates 85 may also undergo Stille-type coupling (Echavarren, A. M., Stille, J. K. J. Am. Chem. Soc., 1987, 109, 5478-5486) with aryl, vinyl, or heterocyclic stannanes 89. Bromides or triflates 85 may also undergo Negishi-type coupling with other aryl or heterocyclic bromides 90 (Negishi E. Accts. Chem. Res. 1982, 15, 340; M. Sletzinger, et al., Tet. Lett. 1985, 26, 2951). Deprotection of the amino group yields an amine which can be coupled to make a urea and other linkers containing Z as described above and for Scheme 1. Amino protecting groups include phthalimide, 2,4-dimethyl pyrrole (S. P. Breukelman, et al. J. Chem. Soc. Perkin Trans. I, 1984, 2801); N-1,1,4,4-Tetramethyldisilyl-azacyclopentane (STABASE) (S. Djuric, J. Venit, and P. Magnus Tet. Lett 1981, 22, 1787) and others familiar to one skilled in the art. 
Many amines are commercially available and can be used as 9, 10, or used as precursors to isocyanates or isothiocyanates 5. There are numerous methods for the synthesis of non-commercially available amines familiar to one skilled in the art. For example, aldehydes and ketones may be converted to their O-benzyl oximes and then reduced with LAH to form an amine (Yamazaki, S.; Ukaji, Y.; Navasaka, K.; Bull Chem Soc Jpn 1986, 59, 525). Ketones and trifluoromethylketones undergo reductive amination in the presence of TiCl4 followed by NaCNBH4 to yield amines (Barney, C. L., Huber, E. W., McCarthy, J. R. Tet. Lett. 1990, 31, 5547-5550). Aldehydes and ketones undergo reductive amination with Na(AcO)3BH as mentioned previously to yield amines (Abdel-Magid, A. F., et al. Tet. Lett. 1990, 31, (39) 5595-5598). Amines may also be synthesized from aromatic and heterocyclic OH groups (for example, phenols) via the Smiles rearrangement (Weidner, J. J., Peet, N. P. J. Het. Chem., 1997, 34, 1857-1860). Azide and nitrile displacements of halides, tosylates, mesylates, triflates, etc. followed by LAH or other types or reduction methods yield amines. Sodium diformyl amide (Yinglin, H., Hongwen, H. Synthesis 1989 122), potassium phthalimide, and bis-BOC-amine anion can all displace halides, tosylates, mesylates, etc., followed by standard deprotection methods to yield amines, procedures which are familiar to one skilled in the art. Other methods to synthesize more elaborate amines involve the Pictet-Spengler reaction, imine/immonium ion Diels-Alder reaction (Larsen, S. D.; Grieco, P. A. J. Am. Chem. Soc. 1985, 107, 1768-69; Grieco, P. A., et al., J. Org. Chem. 1988, 53, 3658-3662; Cabral, J. Laszlo, P. Tet. Lett. 1989, 30, 7237-7238; amide reduction (with LAH or diborane, for example), organometallic addition to imines (Bocoum, A. et al., J. Chem. Soc. Chem. Comm. 1993, 1542-4) and others all of which are familiar to one skilled in the art.
Compounds containing an alcohol side-chain alpha to the nitrogen of the piperidine/pyrrolidine ring can be synthesized as shown in Scheme 18. Only the piperidine case is exemplified, and it is to be understood by one skilled in the art that the alpha-substituted pyrrolidines may be synthesized by a similar route. It is also understood that appropriate substituents may be present on the piperidine/pyrrolidine ring. A 4-benzylpiperidine 91 is protected with a BOC group. The BOC-piperidine 92 is then metallated under conditions similar to those Beak, et al. (P. Beak and W. -K. Lee, J. Org. Chem. 1990, 55, 2578-2580, and references therein) and quenched with an aldehyde to yield alcohol 93. The metallation may also be done enantioselectively using sparteine (P. Beak, S. T. Kerrick, S. Wu, J. Chu J. Am. Chem. Soc. 1994, 116, 3231-3239). This alcohol can be deprotonated with NaH and cyclized to carbamates 94 and 95 which permits structural assignments of the erythro and threo isomers. Protection of the hydroxyl group (93a) followed by deprotection with base yields piperidine 96. We have chosen piperidine only for demonstration purposes. Subsequent acylation or sulfonation by an E group, elaboration to the urea or its isostere and eventual deprotection of the hydroxyl group yields the compounds of this invention. 
Compounds where Zxe2x95x90Nxe2x80x94CN, CHNO2, and C(CN)2 can be synthesized by the methods shown in Scheme 19. Thus amine 100 reacts with malononitrile 99 neat or in an inert solvent at room temperature to the reflux temperature of the solvent, or at the melting point of the solid/solid mixture, to yield malononitrile 98. This in turn can undergo reaction with amine 97 under similar conditions stated just above to yield malononitrile 101. Likewise, a similar reaction sequence may be used to make 104 and 107 [for Zxe2x95x90C(CN)2], see for example P. Traxler, et al., J. Med. Chem. (1997), 40, 3601-3616; for Zxe2x95x90Nxe2x80x94CN, see K. S. Atwal, J. Med. Chem. (1998) 41, 271; for Zxe2x95x90CHNO2, see J. M. Hoffman, et al., J. Med. Chem. (1983) 26, 140-144). For all of the above-mentioned urea isosteres in Scheme 19, the reaction sequence can be reversed. For example, malononitrile 99 can react first with 97 followed by 100 to yield 101. The same holds true for nitroethylene 102 and cyanoguanidine intermediate 106. 
The synthesis of compounds wherein R11 and R12 are taken together to form a heterocyclic ring (such as in 108-111) is outlined in Scheme 20. Thus, 1-[(1,1-dimethylethoxy)carbonyl]-4-[[(phenylmethoxy)carbonyl]amino]-4-piperidineacetic acid 112 (Suzuki, T.; Imanishi, N.; Itahana, H.; Watanuki, S.; Ohta, M.; Mase, T. Synthetic Comm.1998,28, 701-712.) is coupled to (S)-3-(4-fluorobenzyl) piperidine using a common amide forming reagent such as BOP, HBTU or HATU to furnish the amide 113. The CBZ group of 113 can be removed by hydrogenation. Coupling with 3-acetylbenzene isocyanate furnishes 108. One can also use carbamic acid phenyl esters to furnish other urea analogs at this step. In addition, one can synthesize the other urea isosteres (cyanoguanidine, nitroethylene, etc.) covered in this application using the appropriate starting materials mentioned in Scheme 19 at this particular synthetic step. The BOC group of 108 is then removed by TFA or by other methods familiar to one skilled in the art to afford 109, followed by reductive amination to give 110. Reductive amination can also be performed with other aldehydes to yield analogs of compound 110. Compound 109 can be treated with methylsulfonyl chloride to provide methanesulfonamide 111. Likewise, other sulfonylchlorides can be also used at this step to yield a variety of different sulfonamide derivatives. Amine 109 can also be coupled (Schotten-Baumann reaction, using coupling reagents such as BOP, pyBOP, HATU, DCC, EDC, etc.) to a wide variety of carboxylic acids to yield amide derivatives (not shown). 
The synthesis of compounds wherein R11 and R12 is a carboxamide (such as in compound 115) is shown in Scheme 21. Note that if the protecting group on the COOH group of 116 is moved to the other COOH group, then compounds in which R9 or R10 is a carboxamide can be synthesized. Thus (S)-3-(4-fluorobenzyl)piperidine and CBZ-L-ASP(OH)-O-t-Bu is treated with a common amide formation reagent such as BOP, HATU, and TBTU to furnish the coupled product 117. The CBZ group of 117 was removed by hydrogenation. The free amine is then condensed with [3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-carbamic acid phenyl ester to afford the 119. One can use other carbamic acid phenyl esters to furnish other urea analogs. One can also synthesize the other urea isosteres (cyanoguanidine, nitroethylene, etc.) covered in this application using the appropriate starting materials mentioned in Scheme 19 at this particular synthetic step. The tert-butyl group of 119 is then removed by TFA or by other methods familiar to one skilled in the art, followed by coupling with diethylamine in the presence of BOP (or other coupling reagent such as pyBOP, EDC, HATU, DCC, etc.) to afford the final product 115. Note that other amines besides diethylamine can be coupled to provide a wide variety of amides. Coupling with alcohols will yield a wide variety of esters. 
The synthesis of compounds wherein R11 and R12 is an amine (such as in 120) is outlined in Scheme 22. Note that if the protecting group on the COOH group of 121 is moved to the other COOH group, then compounds in which R9 or R10 is an amine can be synthesized. Thus CBZ-L-Asp (tert-butyl)-OH 121 is condensed with morpholine using an amide coupling reagent such as BOP (Note that other amines besides morpholine can be used at this step. In addition, other coupling reagents such as pyBOP, HATU, DCC, EDC, etc. can also be used). The resulting amide 122 is reduced to the corresponding amine, followed by treatment with TFA to afford the carboxylic acid 123. The acid is then coupled with (S)-3-(4-fluorobenzyl)piperidine using BOP (or any of the coupling reagents mentioned previously) to provide 124. The CBZ group of 124 is removed by hydrogenation. Condensation with [3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-carbamic acid phenyl ester furnishes 120. One can use other carbamic acid phenyl esters to furnish other urea analogs. One can also synthesize the other urea isosteres (cyanoguanidine, nitroethylene, etc.) covered in this application using the appropriate starting materials mentioned in Scheme 19 at this particular synthetic step. 
The synthesis of compounds 124 and 127 is described in Scheme 23. Coupling of pyrrolidine/piperidine 1 with a crotonic acid derivative using PyBOP or other peptide coupling reagents yields 121 where R11 or R12 contains a carbon atom which is directly attached to the olefin. It is to be understood that R11 or R12 is in its final form or in a protected form or in the form of a precursor. Michael-type addition of chiral benzyl-(xcex1-methyl benzyl)amine under the conditions of Davies et. al (M. E. Bunnage; A. N. Chernega; S. G. Davies; C. J. Goodwin J. Chem. Soc. P1, (1994) 2373-2384) yields 122. If the intermediate is quenched with a Davis oxaziridine reagent, then xcex1-hydroxylated 125 is obtained. Catalytic hydrogenation over a noble metal catalyst such as Pd(OH)2 yields amides 123 and 126. Coupling as described previously yields 124 and 127. The above sequence may also be performed on crotonate derivative 128 where R is an ester such as methyl, ethyl, t-butyl, etc., but not limited thereto. Eventually the ester is hydrolyzed and coupled to 1 to yield amides 122 and 125. Elaboration as described above yields 124 and 127. 
The synthesis of compounds wherein R9 is a modified amino group (R10xe2x95x90H) is shown in scheme 24. Compound 1 can be coupled to protected diaminopropionic acid 128 using a common amide forming reagent such as PyBOP, HATU or HBTU to furnish the amide 129. Selective removal of protecting group P1 provides amine 130, which can be converted into 131 as urea (Zxe2x95x90O)or thiourea (Zxe2x95x90S)or other urea mimics (Zxe2x95x90Nxe2x80x94CN, CHNO2, and C(CN)2) via the general methods described in Schemes 1 and 19. Deprotection of amino group in 131 provides amine 132. The free amine can be then converted into 133 as an amide, sulfonamide, secondary or tertiary amine, etc. by procedures familiar to one skilled in the art.